1. Field of the Invention
This invention relates to a novel polypeptide designated DPK-1 and related polypeptides that have an effect on apoptosis, to novel nucleic acid molecules encoding such polypeptides, and to other related aspects.
2. Description of Related Art
Normal development and tissue homeostasis in animals require the total cell numbers to be kept in an appropriate range. This is achieved by several highly regulated processes involving cell proliferation, survival, and elimination through programmed cell death (apoptosis). An imbalance between the rates of cell production and cell loss can result in serious human diseases such as cancer, disorders of the immune system, and neurodegenerations (reviewed by Rudin and Thompson, 1997).
Apoptosis appears to be an evolutionarily conserved, highly organized program of active cell destruction (reviewed by Miura and Yuan, 1996; Vaux and Strasser, 1996). In the nematode Caenorhabditis elegans, 14 genes involved in apoptosis have been identified. Among these, the CED-3 gene encodes a cysteine protease of the capsase family and is a key effector in the cell death pathway. The gene product of CED-4 appears to be an adaptor protein which activates CED-3 upon receiving apoptosis signals (Vaux, 1997; Jacobson, 1997). The CED-9 gene, a potent suppresser of programmed cell death, negatively regulates the activity of CED-3, probably through CED-4. In mammalian cells, multiple capsases have been identified and shown to be part of the cell death machinery (Henkart, 1996). The Bcl-2 proto-oncogene appears to be the prototype of mammalian homologs of CED-9 (Vaux et al, 1988; Vaux et al, 1992; Hengartner and Horvitz, 1994).
Other members of the Bcl-2 family consist of those (such as Bcl-XL) that are functionally similar to Bcl-2 which can block apoptosis; and others (Bax, for example) that have the opposite activity (Boise et al, 1993; Oltvai et al, 1993). Although the molecular mechanism is still unclear, recent evidence showed that Bcl-2 can block the release of cytochrome C from mitochondria (Yang et al, 1997; Kluck et al, 1997). In addition, Bcl-2 appears to directly inhibit capsase activation by binding to the mammalian CED-4 homolog (Zou et al, 1997). Other genes besides the Bcl-2 family have also been implicated in programmed cell death as well. For example, the transcription factors c-myc and NFkB may be involved in transducing signals for cell death or survival (Eskew et al, 1991; Evan et al, 1992; Hsu et al, 1995; Beg and Baldwin, 1996; Wang et al, 1996). The tumor suppresser gene p53, which is mutated in over 50% of human cancers, plays an essential role in radiation induced apoptosis in a wide variety of cell types (reviewed by Carson and Lois, 1995).
The cyclin-dependent kinases (CDKs) are a family of related serine/threonine kinases that are associated with and are activated by cyclins (Morgan, 1995). Although the CDKs were originally identified as key regulators of cell division, some newer members of the family clearly have functions outside of cell cycle control. In the budding yeast Saccharomyces cerevisiae, for example, the CDKs encoded by PHO85, KIN28, and SRB10 appear to be involved in transcriptional regulations (Hirst et al, 1994; Kattman et al, 1994; Liao et al, 1995). In mammalian cells, the CDK family currently consists of eight members. Of these, the CDK7/cyclin H complex has been shown to interact with the general transcription machinery (Feaver et al, 1994; Roy et al, 1994; Serizawa et al, 1995 Shiekhattar et al, 1995); and the primary target of CDK5 appears to be the neurofilament proteins (Hellmich et al, 1992; Shetty et al, 1993). The protein encoded by human CDK8 associates with cyclin C, an atypical cyclin which does not oscillate during cell cycle (Tassan et al, 1995). More recently, it was reported that Drosophila CDK8 can interact with and phosphorylate the large subunit of RNA polymerase II (Leclerc et al, 1996). Based on these results and the sequence similarities to the yeast SRB10/SRB11 pair, it was postulated that the CDK8/Cyclin C complex may play a role in transcriptional regulation.
Although a number of cell death related genes and proteins are now known, there remains a need to identify additional such genes and proteins and to determine their biological activity.
Accordingly, it is an object of the present invention to provide novel compounds that are associated with cell death in mammals.
It is a further object of the invention to provide a method of treating diseases associated with cell death such as those set forth herein.
These and other objects will be apparent to one of ordinary skill in the art from the present disclosure.